XRCC7 (DNA-PKcs) - DNA-Dependent Protein Kinase Catalytic Subunit

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XRCC7 (DNA-PKcs) - DNA-Dependent Protein Kinase Catalytic Subunit

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XRCC7 (DNA-PKcs) — DNA-Dependent Protein Kinase Catalytic Subunit

Introduction

XRCC7, also known as DNA-PKcs (DNA-dependent protein kinase catalytic subunit), encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex. DNA-PK is a central component of the non-homologous end joining (NHEJ) pathway, the predominant mechanism for repairing DNA double-strand breaks (DSBs) in mammalian cells. This gene is essential for maintaining genomic integrity in all cells, with particular importance in [neurons](/entities/neurons) where DNA repair defects have been implicated in [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), and other neurodegenerative conditions.

Gene Overview

| Attribute | Value |
|-----------|-------|
| Gene Symbol | XRCC7 (DNA-PKcs) |
| Full Name | X-Ray Repair Cross-Complementing 7 / DNA-PK Catalytic Subunit |
| Chromosomal Location | 8q24.21 |
| NCBI Gene ID | 5591 |
| OMIM | 604743 |
| Ensembl ID | ENSG00000137413 |
| UniProt | P78527 |
| Protein Length | 4128 amino acids |
| Protein Class | Serine/threonine protein kinase |
| Molecular Weight | ~469 kDa |

...

XRCC7 (DNA-PKcs) — DNA-Dependent Protein Kinase Catalytic Subunit

Introduction

XRCC7, also known as DNA-PKcs (DNA-dependent protein kinase catalytic subunit), encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex. DNA-PK is a central component of the non-homologous end joining (NHEJ) pathway, the predominant mechanism for repairing DNA double-strand breaks (DSBs) in mammalian cells. This gene is essential for maintaining genomic integrity in all cells, with particular importance in [neurons](/entities/neurons) where DNA repair defects have been implicated in [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), and other neurodegenerative conditions.

Gene Overview

| Attribute | Value |
|-----------|-------|
| Gene Symbol | XRCC7 (DNA-PKcs) |
| Full Name | X-Ray Repair Cross-Complementing 7 / DNA-PK Catalytic Subunit |
| Chromosomal Location | 8q24.21 |
| NCBI Gene ID | 5591 |
| OMIM | 604743 |
| Ensembl ID | ENSG00000137413 |
| UniProt | P78527 |
| Protein Length | 4128 amino acids |
| Protein Class | Serine/threonine protein kinase |
| Molecular Weight | ~469 kDa |

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">XRCC7 (DNA-PKcs) Gene Information</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>XRCC7 (DNA-PKcs)</td></tr>
<tr><td><strong>Full Name</strong></td><td>X-Ray Repair Cross-Complementing 7 / DNA-PK Catalytic Subunit</td></tr>
<tr><td><strong>Chromosome</strong></td><td>8q24.21</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>5591</td></tr>
<tr><td><strong>OMIM</strong></td><td>604743</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000137413</td></tr>
<tr><td><strong>UniProt</strong></td><td>P78527</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Ataxia-telangiectasia, SCID, Cancer</td></tr>
</table>
</div>

Discovery and Nomenclature

XRCC7 was identified through complementation studies of X-ray-sensitive Chinese hamster ovary (CHO) cell lines. The gene product was later characterized as the catalytic subunit of DNA-dependent protein kinase, hence the alternate name DNA-PKcs. The XRCC (X-ray repair cross-complementing) nomenclature reflects its original identification in radiation sensitivity screens.

Protein Structure

DNA-PKcs is one of the largest known proteins and belongs to the phosphatidylinositol 3-kinase-related kinase (PIKK) family[@goodwin2019]. Its structure includes:

Structural Domains

N-terminal region

HEAT repeats (Hungarian for "spiral")
Flexibly linked arm segments
Contains the DNA-binding channel

Kinase domain (residues 2600-3800)

Catalytic core with typical kinase motifs
Phosphorylation sites for activation
ATP-binding pocket

C-terminal region

FAT (FRAP-ATM-TRRAP) domain
PRD (PIKK regulatory domain)
FATC (C-terminal) domain

Nucleic acid binding regions

DNA-binding channel
Ku70/80 interaction surfaces

Post-Translational Modifications

Phosphorylation: Multiple serine/threonine sites
Acetylation: Lysine modifications
Sumoylation: Regulation of kinase activity
Ubiquitination: Degradation and signaling

The DNA-PK Complex

DNA-PK functions as a holoenzyme composed of:

DNA-PKcs (XRCC7)

The catalytic subunit that provides kinase activity.

Ku70/Ku80 Heterodimer

Binds DNA ends with high affinity
Recruits DNA-PKcs to DNA damage sites
Acts as the regulatory component
Forms the "DNA-PK" complex when bound to DNA-PKcs

Complex Assembly

Ku70/80 rapidly binds DNA ends

DNA-PKcs is recruited via Ku interaction

Autophosphorylation activates the complex

Downstream repair factors are recruited

Biological Functions

DNA Double-Strand Break Repair

The primary function of DNA-PK is in the NHEJ pathway[@meeks2020]:

Step 1: DNA end recognition

Ku70/80 binds to DNA double-strand breaks
Rapid diffusion along DNA

Step 2: DNA-PKcs recruitment

Ku recruits DNA-PKcs to the break site
DNA-PKcs positioning on DNA ends

Step 3: Activation

DNA binding stimulates DNA-PKcs autophosphorylation
Kinase activity increases dramatically

Step 4: End processing

Recruitment of Artemis nuclease
Processing of incompatible DNA ends

Step 5: Ligation

XRCC4/LIG4 complex joins DNA ends
DNA-PKcs dissociates from repaired DNA

V(D)J Recombination

DNA-PKcs is essential for V(D)J recombination in developing B and T lymphocytes[@alt2021]:

Generates antigen receptor diversity
Required for proper lymphocyte development
DNA-PKcs deficiency causes severe combined immunodeficiency (SCID)

Transcription Regulation

DNA-PKcs has transcription-related functions:

Modulates RNA polymerase II activity
Regulates transcription factor function
Involved in chromatin remodeling

Cell Cycle Regulation

DNA-PKcs contributes to checkpoint signaling
Affects cell cycle progression
Regulates p53 activity

Expression Pattern

DNA-PKcs is expressed in virtually all cell types:

Tissue Distribution

Brain: High expression in neurons
Lymphoid tissues: T cells, B cells
Testis: Germ cell development
Proliferating cells: High in S phase

Cellular Localization

Predominantly nuclear: Diffuse nuclear staining
Associated with chromatin: Enrichment at DNA damage sites
Cytoplasmic pool: Minor fraction

Brain Expression

In the central nervous system:

Neurons: High expression in cortex, hippocampus
Astrocytes: Moderate expression
Microglia: Lower expression

Disease Associations

Alzheimer's Disease

DNA-PKcs has emerged as an important player in [Alzheimer's Disease](/diseases/alzheimers-disease)[@anderson2022]:

Pathological involvement:

Neuronal DNA damage accumulation

Increased DSBs in AD brain
Impaired repair capacity
DNA-PKcs dysregulation

Tau pathology

DNA-PKcs phosphorylates tau
Interacts with neurofibrillary tangles
Contributes to tau aggregation

Amyloid interactions

Aβ induces DNA damage
DNA-PKcs activation in response
Contributes to neuronal stress

Synaptic dysfunction

DNA repair defects affect neurons
Cognitive decline correlation

Therapeutic targeting:

DNA-PKcs inhibitors under investigation
Modulation of DNA repair capacity

Parkinson's Disease

In [Parkinson's Disease](/diseases/parkinsons-disease)[@choi2020]:

Dopaminergic neuron vulnerability:

Increased DNA damage in substantia nigra
DNA-PKcs activity alterations
Impaired NHEJ efficiency

Mechanisms:

Mitochondrial DNA damage
Oxidative stress-induced DSBs
Age-related decline in repair

Therapeutic implications:

DNA-PKcs modulators for neuroprotection
Enhancement of DNA repair

Ataxia-Telangiectasia

DNA-PKcs interacts with ATM in AT pathogenesis[@vasquez2021]:

Synergistic effects with ATM deficiency
Contributes to neurodegeneration
DNA damage hypersensitivity

Cancer

DNA-PKcs is frequently overexpressed in cancers:

Oncogenic functions:

Promotes tumor cell survival
Confers radiation resistance
Supports genomic instability

Therapeutic targeting:

DNA-PKcs inhibitors sensitize to radiation[@liu2021]
Combination with PARP inhibitors
Synthetic lethality approaches

Immunodeficiency

Biallelic DNA-PKcs mutations cause[@chen2023]:

Severe combined immunodeficiency (SCID)
V(D)J recombination defects
Radiosensitivity

DNA-PKcs in Brain Aging and Neurodegeneration

Aging Brain

DNA-PKcs activity changes with age[@zhang2019]:

Declining NHEJ efficiency
Accumulation of DNA damage
Contributing to cognitive decline

Synaptic Function

DNA-PKcs has additional roles in synaptic biology[@santiago2022]:

Regulates synaptic plasticity
Affects learning and memory
Neuronal function beyond DNA repair

Circadian Regulation

DNA-PKcs connects DNA repair to circadian rhythm[@kim2020]:

Links DNA damage response to clock
Affects daily rhythms of repair
Implications for neurodegeneration

Therapeutic Implications

Cancer Therapy

DNA-PKcs is a validated cancer target[@kelley2019]:

Radiation sensitization

DNA-PKcs inhibitors enhance RT effect
Lower doses effective
Reduced normal tissue toxicity

Combination approaches

With PARP inhibitors
With chemotherapy
With immunotherapy

Specific inhibitors

Multiple compounds in development
Clinical trials ongoing

Neurodegeneration

Modulating DNA-PKcs in the brain is being explored[@park2023]:

Inhibitors

May reduce pathological activation
Protect neurons from damage

Activators

Enhance DNA repair capacity
Prevent damage accumulation

Gene therapy

Viral vector delivery
Increase expression

Challenges

Blood-brain barrier penetration
Balancing DNA repair in different contexts
Tissue-specific effects

Research Methods

Genetic Studies

Knockout/knockin mice
Conditional deletions
Patient mutation analysis

Biochemical Studies

Kinase activity assays
Phosphorylation analysis
Protein-protein interactions

Cellular Models

Neuronal cultures
Patient-derived cells
iPSC models

Animal Models

DNA-PKcs-deficient mice
Transgenic overexpression
Disease models

Key Publications

[Goodwin et al., DNA-PKcs in DNA damage response and neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31103918/)

[Mahan et al., DNA-PKcs function in neurons (2018)](https://pubmed.ncbi.nlm.nih.gov/29969180/)

[Kelley et al., DNA-PKcs inhibitors as cancer therapeutics (2019)](https://pubmed.ncbi.nlm.nih.gov/30787018/)

[Meek et al., DNA-PKcs phosphorylation and signaling (2020)](https://pubmed.ncbi.nlm.nih.gov/32107647/)

[Alt et al., DNA-PKcs and V(D)J recombination (2021)](https://pubmed.ncbi.nlm.nih.gov/34028022/)

[Anderson et al., DNA damage and repair in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35859034/)

[Choi et al., DNA-PKcs in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/33110072/)

[Vasquez et al., DNA-PKcs and ataxia-telangiectasia (2021)](https://pubmed.ncbi.nlm.nih.gov/34089068/)

[Zhang et al., DNA-PKcs in aging brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31131416/)

[Liu et al., DNA-PKcs inhibitors sensitize cancer to radiation (2021)](https://pubmed.ncbi.nlm.nih.gov/33835847/)

[Kim et al., DNA-PKcs and circadian rhythm regulation (2020)](https://pubmed.ncbi.nlm.nih.gov/32942241/)

[Santiago et al., DNA-PKcs in synaptic function and cognition (2022)](https://pubmed.ncbi.nlm.nih.gov/35671289/)

[Chen et al., DNA-PKcs mutations in immunodeficiency (2023)](https://pubmed.ncbi.nlm.nih.gov/37154218/)

[Park et al., Targeting DNA-PKcs in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37271234/)

External Links

[NCBI Gene: XRCC7](https://www.ncbi.nlm.nih.gov/gene/5591)
[UniProt: P78527](https://www.uniprot.org/uniprot/P78527)
[Ensembl: ENSG00000137413](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137413)
[OMIM: 604743](https://www.omim.org/entry/604743)
[PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=XRCC7+DNA-PKcs)

References

[Goodwin et al., DNA-PKcs in the DNA damage response and neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31103918/)

[Mahan et al., DNA-PKcs function in neurons and neurodegenerative disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29969180/)

[Kelley et al., DNA-PKcs inhibitors as cancer therapeutics (2019)](https://pubmed.ncbi.nlm.nih.gov/30787018/)

[Meek et al., DNA-PKcs phosphorylation and signaling (2020)](https://pubmed.ncbi.nlm.nih.gov/32107647/)

[Alt et al., DNA-PKcs and V(D)J recombination (2021)](https://pubmed.ncbi.nlm.nih.gov/34028022/)

[Anderson et al., DNA damage and repair in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35859034/)

[Choi et al., DNA-PKcs in Parkinson's disease dopaminergic neurons (2020)](https://pubmed.ncbi.nlm.nih.gov/33110072/)

[Vasquez et al., DNA-PKcs and ataxia-telangiectasia (2021)](https://pubmed.ncbi.nlm.nih.gov/34089068/)

[Zhang et al., DNA-PKcs in aging brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31131416/)

[Liu et al., DNA-PKcs inhibitors sensitize cancer to radiation (2021)](https://pubmed.ncbi.nlm.nih.gov/33835847/)

[Kim et al., DNA-PKcs and circadian rhythm regulation (2020)](https://pubmed.ncbi.nlm.nih.gov/32942241/)

[Santiago et al., DNA-PKcs in synaptic function and cognition (2022)](https://pubmed.ncbi.nlm.nih.gov/35671289/)

[Chen et al., DNA-PKcs mutations in immunodeficiency (2023)](https://pubmed.ncbi.nlm.nih.gov/37154218/)

[Park et al., Targeting DNA-PKcs in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37271234/)

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Related Entities

XRCC7

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slug	genes-xrcc7
kg_node_id	XRCC7
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-01599c0b59e9
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-xrcc7'}
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

60%

Debates

0

Incoming

12

Outgoing

15

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

XRCC7 (DNA-PKcs) - DNA-Dependent Protein Kinase Catalytic Subunit

XRCC7 (DNA-PKcs) — DNA-Dependent Protein Kinase Catalytic Subunit

Introduction

Gene Overview

XRCC7 (DNA-PKcs) — DNA-Dependent Protein Kinase Catalytic Subunit

Introduction

Gene Overview

Discovery and Nomenclature

Protein Structure

Structural Domains

Post-Translational Modifications

The DNA-PK Complex

DNA-PKcs (XRCC7)

Ku70/Ku80 Heterodimer

Complex Assembly

Biological Functions

DNA Double-Strand Break Repair

V(D)J Recombination

Transcription Regulation

Cell Cycle Regulation

Expression Pattern

Tissue Distribution

Cellular Localization

Brain Expression

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Ataxia-Telangiectasia

Cancer

Immunodeficiency

DNA-PKcs in Brain Aging and Neurodegeneration

Aging Brain

Synaptic Function

Circadian Regulation

Therapeutic Implications

Cancer Therapy

Neurodegeneration

Challenges

Research Methods

Genetic Studies

Biochemical Studies

Cellular Models

Animal Models

Key Publications

See Also

External Links

References

💬 Discussion